Copyright © 2010 Pearson Education, Inc. Organic Chemistry, 7 th Edition L. G. Wade, Jr. Amines
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Copyright © 2010 Pearson Education, Inc.
Organic Chemistry, 7th Edition L. G. Wade, Jr.
Amines
• Amines are formally derivatives of
ammonia, wherein one or more
hydrogen atoms have been replaced
by a substituent such as an alkyl or
aryl group (these may respectively
be called alkylamines and
arylamines; amines in which both
types of substituent are attached to
one nitrogen atom may be called
alkylarylamines).
• Classification of amines
• Primary (1): Has one alkyl group bonded to the nitrogen (RNH2).
• Secondary (2): Has two alkyl groups bonded to the nitrogen (R2NH).
• Tertiary (3): Has three alkyl groups bonded to the nitrogen (R3N).
• Quaternary (4): Has four alkyl groups bonded to the nitrogen and the nitrogen bears a positive charge(R4N
+).2
3
IUPAC Names
Name is based on longest carbon chain.
-e of alkane is replaced with -amine.
Substituents on nitrogen have N- prefix.
3-bromo-1-pentanamine N,N-dimethyl-3-hexanamine
NH2CH2CH2CHCH2CH3
Br
CH3CH2CHCH2CH2CH3
N(CH3)2
4
Common Names
In aromatic
amines, the amino
group is bonded to
a benzene ring.
Parent compound
is called niline.
5
Heterocyclic AminesWhen naming a cyclic amine the nitrogen is
assigned position number 1.
6
Amine as Substituent
On a molecule with a higher priority functional
group, the amine is named as a substituent.
7
Biologically Active Amines
The alkaloids are an important group of biologically active amines, mostly synthesized by plants to protect them from being eaten by insects and other animals.
Many drugs of addiction are classified as alkaloids.
Dopamine is a neurotransmitter.
Epinephrine is a bioregulator.
Niacin, Vitamin B6, is an amine.
Alkaloids: nicotine, morphine, cocaine
Amino acids
8
Structure of Amines
Nitrogen is sp3 hybridized with a lone pair of electrons.
The angle is less than 109.5º.
9
Boiling Points
N—H less polar than O—H.
Weaker hydrogen bonds, so amines will have a lower
boiling point than the corresponding alcohol.
Tertiary amines cannot hydrogen-bond, so they have
lower boiling points than primary and secondary
amines.
10
Solubility and Odor
Small amines (< 6 Cs) are soluble in water.
All amines accept hydrogen bonds from water
and alcohol.
Branching increases solubility.
Most amines smell like rotting fish.
1,5-pentanediamine or cadaverine
NH2CH2CH2CH2CH2CH2NH2
11
Basicity of Amines
Lone pair of electrons on nitrogen can
accept a proton from an acid.
Aqueous solutions are basic to litmus.
Ammonia pKb = 4.74
Alkyl amines are usually stronger bases
than ammonia.
Increasing the number of alkyl groups
decreases solvation of ion, so 2 and 3
amines are similar to 1 amines in basicity.
12
Alkyl Group Stabilization of Amines
Alkyl groups make the nitrogen a stronger
base than ammonia.
13
Reactivity of Amines
14
Resonance Effects
Any delocalization of the electron pair weakens the base.
15
Protonation of Pyrrole
When the pyrrole nitrogen is protonated,
pyrrole loses its aromatic stabilization.
Therefore, protonation on nitrogen is
unfavorable and pyrrole is a very weak base.
16
Hybridization Effects
Pyridine is less basic than aliphatic amines,
but it is more basic than pyrrole because it
does not lose its aromaticity on protonation.
Hückel's Rule
17
The molecule is cyclic (a ring of atoms)
The molecule is planar (all atoms in the molecule lie
in the same plane)
The molecule is fully conjugated(p orbitals at every
atom in the ring)
The molecule has 4n+2π electrons (n=0 or any
positive integer)
http://chemwiki.ucdavis.edu/Organic_Chemistry/Hydrocarbons/Arenes/Properties_of_Arenes/Aromaticity/H
%C3%BCckel's_Rule
18
Reaction of Amines with Carbonyl
Compounds
19
Electrophilic Substitution
of Aniline
—NH2 is strong activator, ortho- and
para-directing.
Multiple alkylation is a problem.
Protonation of the amine converts the
group into a deactivator (—NH3+).
Attempt to nitrate aniline may burn or
explode.
20
Protonation of Aniline in
Substitution Reactions
Strongly acidic reagents protonate the amino group, giving an ammonium salt.
The —NH3+ group is strongly deactivating (and meta-
allowing).
Therefore, strongly acidic reagents are unsuitable for substitution of anilines.
21
Orientation and Reactivity Effects of Ring Substituents
Activating Substituents
ortho & para-Orientation
Deactivating Substituents
meta-Orientation
Deactivating
Substituents
ortho & para-
Orientation
–O(–)
–OH
–OR
–OC6H5
–OCOCH3
–NH2
–NR2
–
NHCOCH3
–R
–C6H5
–NO2
–NR3(+)
–PR3(+)
–SR2(+)
–SO3H
–SO2R
–CO2H
–CO2R
–CONH2
–CHO
–COR
–CN
–F
–Cl
–Br
–I
–CH2Cl
–
CH=CHN
O2
22
Electrophilic Substitution
of Pyridine
Strongly deactivated by electronegative N.
Substitutes in the 3-position.
Electrons on N react with electrophile.
23
Electrophilic Aromatic Substitution
of Pyridine
24
Electrophilic Aromatic Substitution
of Pyridine (Continued)
Attack at the 2-position would have an
unfavorable resonance structure in which the
positive charge is localized on the nitrogen.
Substitution at the 2-position is not observed.
25
The Octet Rule is violated in these three scenarios:
1. When there are an odd number of valence electrons
2. When there are too few valence electrons
3. When there are too many valence electrons
The octet rule states that elements gain or lose electrons
to attain an electron configuration of the nearest noble gas.
Noble Gases have complete outer electron shells,
which make them very stable.
Octet Rule
26
Nucleophilic Substitution
of Pyridine
Deactivated toward electrophilic attack.
Activated toward nucleophilic attack.
Nucleophile will replace a good leaving group in the 2- or 4-position.
27
Mechanism for
Nucleophilic Substitution
Attack at the 3-position does not have the
negative charge on the nitrogen, so
substitution at the 3-position is not observed.
28
Acylation of Amines
Primary and secondary amines react with
acid halides to form amides.
This reaction is a nucleophilic acyl
substitution.
29
Acylation of Aromatic Amines
When the amino group of aniline is acetylated, the resulting amide is still activating and ortho, para-directing.
Acetanilide may be treated with acidic (and mild oxidizing) reagents to further substitute the ring.
The acyl group can be removed later by acidic or basic hydrolysis.
30
Show how you would accomplish the following synthetic conversion in good yield.
Problem 1
31
Formation of Sulfonamides
Primary or secondary amines react with
sulfonyl chloride.
32
Synthesis of Sulfanilamide
33
Hofmann Elimination
A quaternary ammonium salt has a good
leaving group—a neutral amine.
Heating the hydroxide salt produces the least
substituted alkene.
After the first step, a quaternary ammonium iodide salt is created. After replacement of
iodine by an hydroxyl anion, an elimination reaction takes place to the alkene.
34
Mechanism of the Hofmann Elimination
35
Oxidation of Amines
Amines are easily oxidized, even in air.
Common oxidizing agents: H2O2 , MCPBA.
2 Amines oxidize to hydroxylamine (—NOH)
3 Amines oxidize to amine oxide (R3N+—O-)
36
Preparation of Amine Oxides
Tertiary amines are oxidized to amine oxides,
often in good yields.
Either H2O2 or peroxyacid may be used for
this oxidation.
37
Reductive Amination: 1º Amines
Primary amines result from the condensation of
hydroxylamine (zero alkyl groups) with a ketone or an
aldehyde, followed by reduction of the oxime.
LiAlH4 or NaBH3CN can be used to reduce the oxime.
38
Reductive Amination: 2º Amines
Condensation of a ketone or an aldehyde with a primary amine forms an N-substituted imine (a Schiff base).
Reduction of the N-substituted imine gives a secondary amine.
39
Reductive Amination: 3º Amines
Condensation of a ketone or an aldehyde with a
secondary amine gives an iminium salt.
Iminium salts are frequently unstable, so they are
rarely isolated.
A reducing agent in the solution reduces the iminium
salt to a tertiary amine.
40
Synthesis of 1º Amines by
Acylation–Reduction
Acylation of the starting amine by an acid chloride gives an amide with no tendency toward overacylation.
Reduction of the amide by LiAlH4 gives the corresponding amine.
41
Synthesis of 2º Amines by
Acylation–Reduction
Acylation–reduction converts a primary amine
to a secondary amine.
LiAlH4, followed by hydrolysis, can easily
reduce the intermediate amide to the amine.
42
Synthesis of 3º Amines by
Acylation–Reduction
Acylation–reduction converts a secondary
amine to a tertiary amine.
Reduction of the intermediate amide is
accomplished with LiAlH4.
43
Show how to synthesize N-ethylpyrrolidine from pyrrolidine using acylation–reduction.
Solved Problem 4
44
Reduction of Azides
Azide ion, N3-, is a good nucleophile.
React azide with unhindered 1 or 2 halide
or tosylate (SN2).
Alkyl azides are explosive! Do not isolate.
45
Reduction of Nitriles
Nitrile (CN) is a good SN2 nucleophile.
Reduction with H2 or LiAlH4 converts the
nitrile into a primary amine.
46
Reduction of Nitro Compounds
The nitro group can be reduced to the amine
by catalytic hydrogenation or by an active
metal and H+.
Commonly used to synthesize anilines.
47
The Hofmann Rearrangement of
Amides
In the presence of a strong base, primary amides react with chlorine or bromine to form shortened amines, with the loss of the carbonyl carbon atom.
This reaction, called the Hofmann rearrangement, is used to synthesize primary and aryl amines.
48
Mechanism of the Hofmann
Rearrangement: Steps 1 and 2
49
Mechanism of the Hofmann
Rearrangement: Steps 3 and 4
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